Ischemic mitral regurgitation (MR) is MR that is caused by the left ventricular (LV) remodeling that occurs after postero-basal myocardial infarction (MI). Ischemic MR affects up to 2.1 million patients in the United States and one-year mortality rates for moderate and severe MR is 17 and 40% respectively. It is generally assumed that the LV hypertrophy associated with ischemic MR is caused by volume load and mediated by an increase in diastolic LV wall stress. Further, in order to reduce the diastolic stress associated with ischemic MR, mitral valve (MV) repair is usually proscribed. However, the effect of mitral repair on mitral leaflet and ventricular myofiber stress is poorly understood. More importantly, the effect of ischemic MR on ventricular hypertrophy (remodeling) is the subject of debate. For instance, Gorman and others suggest that mitral valve repair should not be used in patients with ischemic MR because mitral repair fails to slow ventricular remodeling. The proposal will build on our previous experience with cardiac finite element modeling and with MI and reparative operations for heart failure in sheep. In aim 1, we will extend our previous realistic finite element model of the LV to include the mitral valve. That LV/ MR model will be used to calculate regional myocardial LV material properties, LV myofiber stress and LV function before and after valvular MV repair using rigid (`Physio' and dog-bone shaped) and flexible (septo-lateral annular cinch (SLAC)) and subvalvular MV repair including papillary muscle repositioning, infarct plication and passive LV constraint. Ligation of circumflex marginal coronary artery branches 2 and 3 in sheep causes a postero-basal MI and moderate to severe MR. Guy and colleagues found that sheep treated with prophylactic MV repair had LV end- diastolic volume similar to control animals after postero-lateral MI Using this data, Gorman and others suggest that MV repair should not be used in patients with ischemic MR. However, MR is progressive after postero- lateral MI in sheep and animals in Guy's study were only followed for 8 weeks. In aim 2, we will repeat the Guy experiment but with 16 weeks of follow-up. This study should have a major impact on current surgical practice. Last, the non-ischemic infarct extension that occurs in the BZ after antero-apical MI in sheep may also contribute to LV remodeling after postero-lateral MI and ischemic MR. We will measure remodeling strain using an array of sonomicrometry crystals in sheep after postero-basal MI with different levels of diastolic ( ischemic MR) and systolic stress ( ACE inhibitor Ramipril).Enlargement of the heart after a myocardial infarction (MI) may cause the mitral valve to leak (mitral regurgitation). If mitral regurgitation occurs after an MI, patient survival is dramatically reduced. However, it remains unclear whether or how the valve should be fixed. In this grant application, we propose to use sophisticated mathematical simulations in conjunction with animal experiments to determine whether and how mitral regurgitation accelerates cardiac enlargement after an MI and the effect of mitral valve repair on cardiac wall stress. [unreadable] [unreadable] [unreadable]